Though the incidence of synchronous endometrial and ovarian cancers is low, it shouldn’t be omitted as the number of young nulliparous endometrial cancer and ovarian cancer patients is increasing [14, 15]. Our study is the first to report eight patients with concurrent endometrial and ovarian lesions who underwent fertility-sparing management, including 4 SEOCs, 2 BOTs concurrent with EC, and 2BOTs combined with EAH. Looking through the current literature, four SEOC cases were reported to take fertility-sparing therapy [8, 16,17,18], but two of the four cases terminated fertility preservation after confirming SEOC, and one case chose hysterectomy with ovarian conservation after 7-month progesterone therapy in the hope of gestational surrogacy, and the case took staging surgery after oocyte retrieval, and only one patient insisted conservative therapy and succeeded and got spontaneous pregnant after operation and six cycles of chemotherapy. In our study, the complete remission rate was 87.5% (7/8) while only one got NR terminated conservative treatment halfway. The pregnancy rate was 80% (4/5), with four live births. Though successful cases and related experience are limited, fertility-sparing treatment for SEOC patients and concurrent BOTs and EC and EAH patients should be explored further.

Nowadays no standard guidelines in this field, but fertility conservative treatment for SEOCs or concurrent precancerous endometrial and ovarian lesions seems not impossible, according to our study and the published cases. It also seems feasible and explorable from other perspectives. Firstly, limited available data or experience directly supports conservative treatment in SEOCs or concurrent endometrial and ovarian malignancies, but highly selected patients may deserve the try. Tons of evidence has shown that elected patients with early presumed IA EC and EAH can undertake fertility-sparing treatment and get good outcomes [4], which can also be seen in BOTs [19] and some OCs [5, 20] within certain pathological profiles. Secondly, SEOC patients usually have earlier tumor stages, lower pathological grades, and better prognoses, compared to single EC and OC patients [21]. According to previous studies, the estimated 5-year overall survival (OS) of SEOC patients is 79.7-85.9%and 10-year OS is about 72.5-85.6% [3, 22, 23], which is similar to stage I EC without synchronous OC. Though the above data is from patients with staging surgery, its favorable prognosis provides the possibility of fertility preservation for highly selected SEOC patients. The median age of SEOC patients is about 10 years younger than patients with single EC or OC, and about 30% of them have not yet given birth [22]. As stated in 2021 ESGO guidelines [24], indolent behavior of SEOC with low-grade endometrioid carcinoma supports conservative management when the following criteria are met: (a) both tumors are low grade; (b) < 50% myometrial invasion; (c) no involvement of any other site; (d) absence of extensive LVSI at any location. Thirdly, with the development of molecular diagnosis, genetic screening, imaging techniques, and laparoscopy, as well as hysteroscopy, pathologists, and clinicians have more confidence in differentiating synchronous cancers or metastasis, which is of pivotal significance in fertility-preservation management. Based on the above evidence, fertility-sparing treatment is worth trying in this population, though it is challenging.

Risks and challenges coexist. Differentiation between “metastatic” and “synchronous” is the primary determinant before moving towards conservative management. Adnexal involvement by endometrial cancer or uterine involvement by OC is currently an indicator affecting FIGO staging and has an impact on patients’ overall survival rates. Patients with synchronous involvement of the endometrium and ovary by low-grade carcinoma had a favorable outcome [22]. In our study, all four SEOC patients had the synchronous presentation of low-grade endometrioid endometrial and ovarian carcinomas, and one case (Case3) had local dedifferentiated carcinoma in OC. By the way, five cases of ovarian lesions originated from ovarian endometriotic cysts in our study, which also helps pathologists and clinicians judge between “metastatic” and “synchronous”. Though several criteria [25, 26] have been suggested in the past to help distinguish between metastatic tumors and synchronous primary tumors, it is not easy to apply.

And recent studies [27, 28] have indicated that there is a clonal relationship between EC and OC in SEOC patients, the theory of “restricted metastatic potential” or “restricted dissemination” has been proposed by Anglesio [29], and such patients do not need adjuvant therapies [24]. This theory [29] regards that the tumor is isolated from the primary site, and the disseminated tumor is confined to the new site due to the effect of the microenvironment at the new site. The tumor cells detach from a primary site without apoptosis, spread, and recolonize at certain areas under a strict microenvironment without the capacity for further dissemination [27, 29]. Nowadays traditional histological diagnosis is still the most powerful and effective method in the clinic, molecular analysis may also help, and we need to explore more methods in differentiating “metastatic” and “synchronous”.

Besides careful pathological examination, other aspects should also be fully assessed, including patients’ desire for fertility, ovarian function, metabolic conditions, and reliance. No standard treatment is advised. High dosages of high-efficacy progesterone, LNG-IUD, and GnRha were used in our study, but which one is the best choice? We are not sure yet. More studies are needed. The regular hysteroscopic examination is used for endometrium evaluation while imaging and serum biomarkers are used for monitoring potential extra-uterine metastasis. Micro-metastasis or potential progression may be hard to detect at an early stage. We suggest experienced experts and a multiple-disciplinary team participate in treatment, monitoring, and long-term follow-up during the whole period of conservative management, and extensive follow-up should be extended into the periods of assisted reproductive treatment, stages of pregnancy, and post-reproduction. Lots of related problems are needed to be addressed in the future.

In our study, the CR rate (87.5%), the pregnancy rate (80%), and the live birth rate (80%) are promising, and the oncologic and reproductive outcomes are exciting. But long-term outcomes are still unclear, and we will continue to follow up on each case. Besides treating endometrial and ovarian lesions, how to choose the proper ART after CR is also a big challenge, especially during the process of ovarian stimulation. Different studies on the associations between fertility drug use and potential OC risk and endometrial cancer risk are conflicting [30,31,32]. Though most studies showed no meaningful increased risk of invasive OC or uterine cancer related to fertility drug use, those researches mainly focused on the infertility population not affected by genital cancers. There is no robust research focused on fertility drug use in females affected by EEA OC BOTs or SEOC. Limited observations or cohort data are available, so we still need to be cautious when choosing ovulation-stimulating agents for those females. Ovulation stimulation protocols include conventional short agonist regimen, long agonist regimen, antagonist regimen, mild stimulation protocol (usually clomiphene citrate (CC) or letrozole (LE) combined with gonadotropins (Gn)), and progestin-primed ovarian stimulation (PPOS). We prefer PPOS and mild stimulation protocol to other protocols in the hope of minimizing the risk of recurrence. However it’s still not clear which ovarian stimulation protocol is the most effective and safe for those patients, and more in-depth and larger sample studies are needed.

This is a single-center retrospective study. Cases are limited and more cases should be collected and studied to add knowledge to this field. The available evidence is not robust, and more large-scale studies are warranted to induce experience and guidelines in managing young women with early-stage SEOC or coexistence of ovarian and endometrial neoplasms who want to preserve fertility. And the follow-up time is not long enough which may limit our assessment of recurrence and long-term prognosis, and we will continue to follow up.